Fourier-Transform Infrared Spectroscopy (FT-IR) has been used to study conformational changes that occur in solid phase and film phase molecular structures (see e.g., Tomasz et al., Science 235:1204-1208 (1987) and Barth et al., Biochem. Biophys. Acta 1057:115-123 (1991)). However, it has not been apply to drug discovery, particularly in solution phase, with high through-put methods and small amounts of target (fmolar). Problems with high background and peak identification has been some of the reason that FT-IR spectroscopy has had limited fields of use. The present invention provides methods of using FT-IR spectroscopy, particularly differential, microscopic FT-IR spectroscopy, for drug discovery.